WO2012147897A1 - Procédé de production d'un composé aminé - Google Patents

Procédé de production d'un composé aminé Download PDF

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WO2012147897A1
WO2012147897A1 PCT/JP2012/061303 JP2012061303W WO2012147897A1 WO 2012147897 A1 WO2012147897 A1 WO 2012147897A1 JP 2012061303 W JP2012061303 W JP 2012061303W WO 2012147897 A1 WO2012147897 A1 WO 2012147897A1
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group
formula
atom
compound
mmol
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レオポル ンパカ ルテテ
池本　哲哉
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Sumitomo Chemical Co Ltd
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Sumitomo Chemical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to a method for producing an amine compound.
  • Amine compounds such as ⁇ -phenylpropylamine are known to be useful as intermediates for the production of pharmaceuticals, agricultural chemicals and the like.
  • a solid liquid containing a dialkylzinc and an inorganic salt is obtained by reacting a grineer reagent (alkylmagnesium chloride) with dimethoxyzinc in an ether solvent. Then, the solid-liquid mixture is centrifuged or filtered to obtain a dialkylzinc from which inorganic salts have been removed, and the dialkylzinc and N-diphenylphosphinic benzaldimine are used as catalysts for diphosphine monooxide.
  • a method is described in which an N-protected ⁇ -phenylpropylamine is obtained by reacting in the presence of a compound and a copper compound.
  • the diphosphine monooxide compound is known to be sensitive to inorganic salts. Therefore, in the above method, the inorganic salt is removed by centrifugation or filtration before using the diphosphine monooxide compound. Since dialkyl zinc decomposes in the presence of water, it is necessary to carry out filtration or the like while keeping it in an anhydrous state. However, special equipment and equipment for that purpose are required. Therefore, it is desirable not to perform filtration or centrifugation. Under such circumstances, there has been a demand for a new method capable of producing an amine compound without being affected by the presence of an inorganic salt.
  • a zinc compound (4-2) and an imine compound (1) are reacted by mixing a compound represented by formula (hereinafter also referred to as an imine compound (1)), a copper compound, and a phosphoramidite compound.
  • Step (3) Formula (2) obtained in Step (2): (Wherein Z, R, R 1 , R 2 , Q 1 , Q 2 and Q 3 are as defined above.)
  • a step of deprotecting the N-protected amine compound represented by hereinafter also referred to as N-protected amine compound (2)); Including formula (5): (Wherein R, R 1 and R 2 are as defined above.) Or a salt thereof (hereinafter also referred to as amine compound (5)).
  • Step (1) The step of reacting the grinder compound (3-1) and the zinc compound (4-1); and Step (2): including the zinc compound (4-2) obtained in the step (1).
  • a process for producing an N-protected amine compound (2) comprising: Group P1: halogen atom, C 1 -C 12 alkyl group, C 1 -C 12 alkoxy group, C 1 -C 12 alkylthio group, C 1 -C 12 fluorinated alkyl group, C 6 -C 14 aryl group, a nitro group , A cyano group, a C 1 -C 20 hydrocarbyloxycarbonyl group, a protected hydroxyl group and a protected amino group; [3] The production method according to the above [1] or [2], wherein the step (1) is performed in the presence of a chain ether solvent; [4]
  • the phosphoramidite compound has the formula (6): (Wherein, X 3, X 4 and X 5 each independently represent a hydrogen atom, C 1
  • the reaction product of the step (1) is a zinc compound (4-2) and a formula (3-2): X 1 -Mg-X 2 (3-2 ) (In the formula, X 1 and X 2 are as defined in the above [1].)
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1 -C 20 “Hydrocarbon group” means “C 1 -C 20 Alkyl group ",” C 2 -C 20 Alkenyl group “,” C 2 -C 20 Alkynyl group ”,“ C 3 -C 20 Cycloalkyl group ”,“ C 4 -C 20 "Cycloalkenyl group” or "C 6 -C 20 Means an "aryl group”.
  • C 1 -C 20 “Alkyl” means linear or branched alkyl having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl.
  • C 1 -C 12 “Alkyl” means linear or branched alkyl having 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl.
  • C 1 -C 6 Alkyl is preferred.
  • “C 1 -C 6 “Alkyl” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, Examples include neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.
  • C 1 -C 4 “Alkyl” means linear or branched alkyl having 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • C 2 -C 20 “Alkenyl” means straight or branched alkenyl having 2 to 20 carbon atoms, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl.
  • C 2 -C 20 “Alkynyl” means straight-chain or branched alkynyl having 2 to 20 carbon atoms, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl.
  • C 3 -C 20 “Cycloalkyl” means a cyclic alkyl having 3 to 20 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl. And cycloeicosyl. Above all, C 3 -C 12 Cycloalkyl, especially C 3 -C 8 Cycloalkyl is preferred.
  • C 4 -C 20 “Cycloalkenyl” means cyclic alkenyl having 4 to 20 carbon atoms.
  • 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexene-1 -Yl, 2-cyclohepten-1-yl, 2-cycloocten-1-yl, 2-cyclononen-1-yl, 2-cyclodecene-1-yl, 2-cyclododecene-1-yl, 2-cycloeicosene- Examples include 1-yl, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, and 2,5-cyclohexadien-1-yl.
  • C 4 -C 12 Cycloalkenyl in particular C 4 -C 8 Cycloalkenyl is preferred.
  • C 3 -C 20 Cycloalkyl "and" C 4 -C 20 “Cycloalkenyl” may be condensed with a benzene ring. Examples of such groups include 1,2-dihydronaphthalen-1-yl, 1,2-dihydronaphthalen-2-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3. , 4-tetrahydronaphthalen-2-yl, fluoren-9-yl, inden-1-yl.
  • C 6 -C 20 “Aryl group” means an aromatic monocyclic or polycyclic (condensed) hydrocarbon group having 6 to 20 carbon atoms, and examples thereof include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
  • C 6 -C 14 Aryl groups, especially C 6 -C 10 Aryl groups are preferred.
  • C 6 -C 14 “Aryl group” means an aromatic monocyclic or polycyclic (condensed) hydrocarbon group having 6 to 14 carbon atoms, for example, a phenyl group, a 1-naphthyl group, a 2-naphthyl group. , A phenanthryl group, an anthryl group, an acenaphthyl group, and a biphenylyl group. Above all, C 6 -C 10 Aryl groups are preferred.
  • C 6 -C 10 “Aryl group” means an aromatic monocyclic or polycyclic (condensed) hydrocarbon group having 6 to 10 carbon atoms, for example, a phenyl group, a 1-naphthyl group, a 2-naphthyl group. Is mentioned. Of these, a phenyl group is preferred.
  • C 7 -C 14 “Aralkyl” means “C 6 -C 10
  • aryl group” 1 -C 4 Alkyl means, for example, benzyl, 1-phenylethyl, 2-phenylethyl, (1-naphthyl) methyl, (2-naphthyl) methyl, 1- (1-naphthyl) ethyl, 1- (2-naphthyl) Examples include ethyl, 2- (1-naphthyl) ethyl, and 2- (2-naphthyl) ethyl.
  • heterocyclic group means “aromatic heterocyclic group” or “non-aromatic heterocyclic group”.
  • aromatic heterocyclic group refers to aromaticity containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom.
  • examples of the “monocyclic aromatic heterocyclic group” include furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl Group, oxazolyl group, isoxazolyl group, oxadiazolyl group (1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group), thiadiazolyl group (1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group) ), A triazolyl group (1,2,4-triazolyl group, 1,2,3-triazolyl group), a tetrazolyl group, and a triazinyl group.
  • the “fused aromatic heterocyclic group” means that the monocyclic aromatic heterocyclic group is a monocyclic aromatic ring group (preferably a phenyl group or a monocyclic aromatic heterocyclic group).
  • quinolyl group isoquinolyl group, quinazolyl group, quinoxalyl group, benzofuranyl group, benzothienyl group, benzoxazolyl group, benzisoxazolyl group, benzothiazolyl group, benzoisothiazolyl group Group, benzimidazolyl group, benzotriazolyl group, indolyl group, indazolyl group, pyrrolopyridyl group, pyrazolopyridyl group, imidazopyridyl group, thienopyridyl group, pyrrolopyrazinyl group, pyrazolopyrazinyl group, imidazopyrazinyl group, thienopyrazinyl Group, pyrrolopyrimidinyl group, pyrazolopyrimidinyl group, imidazopyrimidinyl group, thie Pyrimidinyl group, and Pirazorochieniru group.
  • non-aromatic heterocyclic group means an aromaticity containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom.
  • examples of the “monocyclic non-aromatic heterocyclic group” include azetidinyl group, pyrrolidinyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, hexamethyleneiminyl group, oxazolidinyl group, thiazolidinyl group, Imidazolidinyl group, oxazolinyl group, thiazolinyl group, imidazolinyl group, dioxolyl group, dioxolanyl group, dihydrooxadiazolyl group, pyranyl group, tetrahydropyranyl group, thiopyranyl group, tetrahydrothiopyranyl group, tetrahydrofuryl group, pyrazolidinyl group, pyrazolinyl group , Tetrahydropyrimidinyl group, dihydrotriazolyl group,
  • the “fused non-aromatic heterocyclic group” means that the above monocyclic non-aromatic heterocyclic group is a monocyclic aromatic ring group (preferably a phenyl group or a monocyclic aromatic heterocyclic group).
  • a ring group obtained by partial saturation of the ring group for example, dihydroindolyl group, dihydroisoindolyl group, dihydrobenzofuranyl group, dihydrobenzothiophenyl group, dihydro Benzodioxinyl group, dihydrobenzodioxepinyl group, tetrahydrobenzofuranyl group, chromenyl group, dihydrochromenyl group, dihydroquinolinyl group, tetrahydroquinolinyl group, dihydroisoquinolinyl group, tetrahydroisoxyl group
  • Examples include a nolinyl group and a dihydrophthalazinyl group.
  • examples of the “monocyclic aromatic heterocycle” include furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole ( 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiadiazole (1,2,4-thiadiazole, 1,3,4-thiadiazole), triazole (1,2,4-triazole, 1,2,3-triazole), tetrazole, and triazine.
  • alkoxy means straight or branched alkoxy having 1 to 12 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, iso Pentyloxy, neopentyloxy, 1-ethylpropyloxy, hexyloxy, isohexyloxy, 1,1-dimethylbutyloxy, 2,2-dimethylbutyloxy, 3,3-dimethylbutyloxy, 2-ethylbutyloxy, Examples include heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy and dodecyloxy.
  • C 1 -C 6 Alkoxy is preferred.
  • alkoxy means straight or branched alkoxy having 1 to 6 carbon atoms, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, iso Pentyloxy, neopentyloxy, 1-ethylpropyloxy, hexyloxy, isohexyloxy, 1,1-dimethylbutyloxy, 2,2-dimethylbutyloxy, 3,3-dimethylbutyloxy, 2-ethylbutyloxy Can be mentioned.
  • C 1 -C 12 “Alkylthio” means linear or branched alkylthio having 1 to 12 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, iso Pentylthio, neopentylthio, 1-ethylpropylthio, hexylthio, isohexylthio, 1,1-dimethylbutylthio, 2,2-dimethylbutylthio, 3,3-dimethylbutylthio, 2-ethylbutylthio, heptylthio , Octylthio, nonylthio, decylthio, undecylthio, dodecylthio.
  • C 1 -C 6 Alkylthio is preferred.
  • “C 1 -C 12 “Fluorinated alkyl” means “C substituted with a fluorine atom” 1 ⁇ 12 Means “alkyl”.
  • the number of fluorine atoms is not particularly limited, and may be perfluoro substituted.
  • “hydrocarbyloxycarbonyl group” means the above-mentioned “C 1 -C 20 It means a group having a structure in which a carbonyl group is bonded to a “hydrocarbon group” through an oxygen atom.
  • “protected hydroxyl group” means a hydroxyl group protected by a “protecting group”. Examples of the “protecting group” include —COQ 1 (Where Q 1 May have at least one group selected from the group P1 1 -C 20 Represents a hydrocarbon group.
  • protecting group examples include acetyl group, trifluoroacetyl group, benzylcarbonyl group, benzoyl group, benzyl group, trityl group, trimethylsilyl group, triethylsilyl group, dimethylphenylsilyl group, tert-butyldimethylsilyl group, tert -A butyl diethyl silyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group is mentioned.
  • the “protected hydroxyl group” include acetoxy group, trifluoroacetoxy group, benzylcarbonyloxy group, benzoyloxy group, benzyloxy group, trityloxy group, trimethylsilyloxy group, triethylsilyloxy group, dimethylphenylsilyl Examples thereof include an oxy group, a tert-butyldimethylsilyloxy group, a tert-butyldiethylsilyloxy group, a 2-tetrahydropyranyloxy group, and a 2-tetrahydrofuranyloxy group.
  • the “protected amino group” means an amino group protected with a “protecting group”.
  • protecting group examples include —COQ 1 , -COOQ 2 Or -SO 2 Q 3 (Where Q 1 , Q 2 And Q 3 Each independently may have at least one group selected from the group P1 1 -C 20 Represents a hydrocarbon group. ) Group, formyl group, C 7 -C 14 Aralkyl group, Benzhydryl group, Trityl group, Tri-C 1 ⁇ 6 Examples thereof include an alkylsilyl group, a 9-fluorenylmethyloxycarbonyl group, and a phthaloyl group.
  • the protecting group include formyl, acetyl, trifluoroacetyl, pivaloyl, tert-butoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyl Oxycarbonyl group, trimethylsilyl group, triethylsilyl group, dimethylphenylsilyl group, tert-butyldimethylsilyl group, tert-butyldiethylsilyl group, 9-fluorenylmethyloxycarbonyl group, benzyl group, benzhydryl group, trityl group, phthaloyl Group, allyloxycarbonyl group, p-toluenesulfonyl group, o-nitrobenzenesulfonyl group.
  • protected amino group examples include formylamino group, acetylamino group, trifluoroacetylamino group, pivaloylamino group, tert-butoxycarbonylamino group, ethoxycarbonylamino group, isopropoxycarbonylamino group, 2 , 2,2-trichloroethoxycarbonylamino group, benzyloxycarbonylamino group, trimethylsilylamino group, triethylsilylamino group, dimethylphenylsilylamino group, tert-butyldimethylsilylamino group, tert-butyldiethylsilylamino group, 9- Fluorenylmethyloxycarbonylamino group, benzylamino group, benzhydrylamino group, tritylamino group, phthaloylamino group, allyloxycarbonylamino group, p-toluenesul
  • the “5- to 9-membered nitrogen heterocycle” includes at least one nitrogen atom other than a carbon atom as a ring-constituting atom, and further a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom
  • a 5- to 7-membered nitrogen-containing heterocyclic ring optionally containing 1 to 2, for example, pyrrolidine, imidazolidine, pyrazolidine, triazolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane, diazepane, oxazepane, Thiazepane, azocane, diazocane, azonan, diazonan can be mentioned.
  • R may preferably have at least one group selected from P1. 1 -C 20 An alkyl group, and more preferably C which may have at least one group selected from P1. 1 -C 12 An alkyl group, and more preferably C which may have at least one group selected from P1. 1 -C 6 An alkyl group, particularly preferably C 1 -C 6 It is an alkyl group.
  • X 1 Is preferably a chlorine atom or a bromine atom.
  • X 2 Is preferably a chlorine atom, a bromine atom or an iodine atom, more preferably a chlorine atom or a bromine atom, still more preferably a chlorine atom.
  • Z is preferably -COOQ 2 (Where Q 2 Is as defined above.
  • R 1 Is preferably C which may have at least one group selected from the group P1.
  • 6 -C 14 An aryl group or an aromatic heterocyclic group optionally having at least one group selected from the group P1, more preferably at least one group selected from the group P1.
  • C 6 -C 10 An aryl group or a 5-membered or 6-membered aromatic heterocyclic group which may have at least one group selected from the group P1.
  • R 2 Is preferably a hydrogen atom.
  • X 3 , X 4 And X 5 Are preferably each independently a hydrogen atom or C 1 -C 12 An alkyl group or X 3 , X 4 And X 5 Adjacent two of them together form a naphthalene ring with the benzene ring to which they are bonded, more preferably each independently a hydrogen atom or C 1 -C 6 An alkyl group or X 3 , X 4 And X 5 Adjacent two of them together form a naphthalene ring with the benzene ring to which they are attached.
  • a 1 And A 2 are preferably each independently C 1 -C 12 It is an alkyl group. Where A 1 And A2 are preferably the same group. A 1 And A 2 Are more preferably each independently C 1 -C 6 It is an alkyl group. A 3 And A 4 Are preferably each independently a phenyl group optionally having at least one group selected from the group P3. Where A 1 And A 2 Are preferably the same group. A 3 And A 4 Are more preferably both phenyl groups.
  • the manufacturing method of the amine compound (5) of this invention includes the following processes.
  • Step (1) a step of reacting the Grineer compound (3-1) and the zinc compound (4-1); Step (2): the reaction product obtained in Step (1) containing the zinc compound (4-2), and an imine A step of reacting compound (4-2) and imine compound (1) by mixing compound (1), a copper compound, and a phosphoramidite compound; and Step (3): a step of deprotecting the N-protected amine compound (2) obtained in Step (2);
  • Step (1) is a step of reacting the grinder compound (3-1) and the zinc compound (4-1).
  • the amount of the grinder compound (3-1) to be used is preferably 1.5 to 2.5 mol, more preferably 1.8 to 2.2 mol, relative to 1 mol of the zinc compound (4-1).
  • the reaction is preferably performed by adding the Grineer compound (3-1) to the zinc compound (4-1).
  • the reaction is preferably carried out in a solvent.
  • Suitable solvents include chain ether solvents such as diethyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, and 1,2-dimethoxyethane; cyclic ether solvents such as cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane. And ether solvents.
  • a chain ether solvent is preferable from the viewpoint of improving reactivity, and diethyl ether or dibutyl ether is particularly preferable.
  • the reaction temperature is preferably ⁇ 20 to 50 ° C., more preferably 0 to 35 ° C., and the reaction time depends on the type and reaction temperature of the grinder compound (3-1) and zinc compound (4-1) used However, it is, for example, 0.5 to 6 hours, preferably 0.5 to 3 hours.
  • a reaction product containing the zinc compound (4-2) and the magnesium compound (3-2) is obtained, but the zinc compound (4-2) is not isolated, and the mixture is left as a mixture in the next step. Used in (2).
  • step (2) the reaction product obtained in step (1) including the zinc compound (4-2), the imine compound (1), the copper compound, and the phosphoramidite compound are mixed.
  • compound (4-2) and imine compound (1) are reacted to obtain N-protected amine compound (2).
  • the amount of zinc compound (4-2) to be used is preferably 2 to 10 mol, more preferably 3 to 6 mol, per 1 mol of imine compound (1).
  • copper (II) trifluoromethanesulfonate, copper (II) trifluoromethanesulfonate-benzene adduct, and copper (I) thiophene-2-carboxylate is preferably 0.01 to 0.2 mol, more preferably 0.03 to 0.1 mol, per 1 mol of the imine compound (1).
  • the phosphoramidite compound is a compound in which two oxygen atoms and one nitrogen atom are bonded to a phosphorus atom.
  • the phosphoramidite compound (6) (Each symbol in the formula is as defined above.) Is mentioned. Suitable phosphoramidite compounds (6) include Etc., among others, Is preferred.
  • the phosphoramidite compound (6) is preferably 0.01 to 0.25 mol, more preferably 0.04 to 0.12 mol, relative to 1 mol of the imine compound (1). Since the phosphoramidite compound (6) is not affected by the magnesium compound (3-2) present in the reaction product containing the zinc compound (4-2), the zinc compound (4-2) is simply removed in the step (1).
  • the zinc compound (4-2) can be used for the reaction in a stable state without being decomposed.
  • the reaction is usually performed by adding an imine compound (1), a copper compound and a phosphoramidite compound to a reaction product containing a zinc compound (4-2).
  • the reaction is preferably performed in a solvent.
  • Suitable solvents include chain ether solvents such as diethyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, and 1,2-dimethoxyethane; cyclic ether solvents such as cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane. And ether solvents.
  • chain ether solvents such as diethyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, and 1,2-dimethoxyethane
  • cyclic ether solvents such as cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane.
  • ether solvents a solvent containing 1,4-dioxane (preferably 1,4-dioxane and a chain ether) from the viewpoint of high solubility of the zinc compound (4-2) and low so
  • a mixture of solvents is preferred.
  • the reaction temperature is preferably ⁇ 78 to 0 ° C., more preferably ⁇ 50 to ⁇ 20 ° C., and the reaction time is that of the zinc compound (4-2), imine compound (1), copper compound or phosphoramidite compound.
  • the type and reaction temperature for example, 0.5 to 24 hours, preferably 1 to 15 hours.
  • the N-protected amine compound (2) thus obtained can be isolated and purified by a conventional method.
  • the N-protected amine compound (2) can be isolated and purified after the extraction operation or by subjecting the reaction mixture directly to silica gel column chromatography.
  • the optically active N-protected amine compound (2) can be obtained by using the optically active phosphoramidite compound (6) (provided that R 1 , R 2 And R are all different groups).
  • the formula (6-S) When a compound represented by formula (2-S) is used: N-protected amine compound (hereinafter also referred to as N-protected amine compound (2-S)) represented by formula (6-R): When a compound represented by the formula (2-R) is used: Is obtained (hereinafter also referred to as N-protected amine compound (2-R)).
  • the optically active phosphoramidite compound (6) enantioselectivity with an enantiomeric excess of, for example, 50 ee% or more, for example, 80 ee% or more is possible.
  • the N-protected amine compound (2) obtained in the step (2) is deprotected to obtain an amine compound (5).
  • the deprotection reaction is performed by a known method according to the type of Z group that is a protecting group.
  • the Z group is C 1 -C 20
  • an ether for example, diethyl ether, dibutyl ether, cyclopentyl methyl ether
  • an ester for example, ethyl acetate
  • an alcohol for example, methanol, ethanol, 2- (Propanol) solution
  • hydrochloric acid having a concentration higher than 3 mol / L (for example, 50 ° C. or more) to give an amine compound.
  • an amine compound (5) is obtained.
  • C 7 -C 20 In the case of an aralkyloxy-carbonyl group (for example, benzyloxycarbonyl etc.), an amine compound (5) is obtained by catalytic reduction.
  • the amine compound (5) thus obtained can be isolated and purified by a conventional method.
  • the N-protected amine compound (2) can be isolated and purified after the extraction operation or by subjecting the reaction mixture directly to silica gel column chromatography. When the optically active N-protected amine compound (2) is used, the configuration of the N-protected amine compound (2) is maintained as it is in the deprotection reaction.
  • the amine compound (5) may be in the form of a salt.
  • Such salts include, for example, inorganic acid salts (eg, hydrochloride, sulfate, nitrate, phosphate); organic acid salts (eg, acetate, propionate, methanesulfonate, 4-toluenesulfonate, Oxalate, maleate); alkali metal salts (eg sodium salt, potassium salt); alkaline earth metal salts (eg calcium salt, magnesium salt); organic base salts (eg trimethylamine salt, triethylamine salt, pyridine salt, picoline salt) Salt, dicyclohexylamine salt).
  • inorganic acid salts eg, hydrochloride, sulfate, nitrate, phosphate
  • organic acid salts eg, acetate, propionate, methanesulfonate, 4-toluenesulfonate, Oxalate, maleate
  • alkali metal salts eg sodium salt, potassium salt
  • the optical activity means that it is not an equivalent mixture (for example, racemate) of isomers having different steric configurations in the asymmetric carbon, and when one stereoisomer is present in excess (for example, a 6: 4 mixture) is defined as optical activity.
  • Example 1 Preparation of diethylzinc from ethylmagnesium chloride and zinc chloride and asymmetric addition to imine 1a in diethyl ether
  • a 1.0 M zinc chloride diethyl ether solution (4.5 mL, 4.5 mmol) was diluted with diethyl ether (17.8 mL), and a 2.0 M ethylmagnesium chloride diethyl ether solution (4.4 mL, 8.8 mmol) was added. added.
  • the resulting suspension was stirred at room temperature for 1 hour, then treated with 1,4-dioxane (2.7 mL), stirred for an additional hour, and then cooled to -35 ° C.
  • Example 3 Preparation of diethylzinc from ethylmagnesium bromide and zinc chloride and asymmetric addition to imine 1a in diethyl ether A 1.0 M zinc chloride diethyl ether solution (4.5 mL, 4.5 mmol) was diluted with diethyl ether (19.3 mL), and a 3.0 M ethylmagnesium bromide diethyl ether solution (2.9 mL, 8.8 mmol) was added.
  • Example 4 Preparation of diethylzinc from ethylmagnesium bromide and zinc chloride and asymmetric addition to imine 1c in diethyl ether
  • a 1.0 M zinc chloride diethyl ether solution (4.5 mL, 4.5 mmol) was diluted with diethyl ether (19.3 mL), and a 3.0 M ethylmagnesium bromide diethyl ether solution (2.9 mL, 8.8 mmol) was added. added.
  • the resulting suspension was stirred at room temperature for 1 hour, then treated with 1,4-dioxane (2.7 mL), stirred for an additional hour, and then cooled to -35 ° C.
  • Example 5 Preparation of diethylzinc from ethylmagnesium chloride and zinc chloride and asymmetric addition to imine 1c in diethyl ether
  • a 1.0 M zinc chloride diethyl ether solution (4.5 mL, 4.5 mmol) was diluted with diethyl ether (19.3 mL), and a 2.0 M ethylmagnesium chloride diethyl ether solution (4.4 mL, 8.8 mmol) was added. added.
  • the resulting suspension was stirred at room temperature for 1 hour, then treated with 1,4-dioxane (2.7 mL), stirred for an additional hour, and then cooled to -35 ° C.
  • Example 6 Preparation of diethylzinc from ethylmagnesium chloride and zinc chloride and asymmetric addition to imine 1b in diethyl ether
  • a 1.0 M zinc chloride diethyl ether solution (4.5 mL, 4.5 mmol) was diluted with diethyl ether (17.8 mL), and a 2.0 M ethylmagnesium chloride diethyl ether solution (4.4 mL, 8.8 mmol) was added. added.
  • the resulting suspension was stirred at room temperature for 1 hour, then treated with 1,4-dioxane (2.7 mL), stirred for an additional hour, and then cooled to -35 ° C.
  • Example 8 Preparation of diethylzinc from ethylmagnesium chloride and zinc chloride and asymmetric addition to imine 1d in diethyl ether
  • a 1.0 M zinc chloride diethyl ether solution (9.0 mL, 9.0 mmol) was diluted with diethyl ether (35.6 mL), and a 2.0 M ethylmagnesium chloride diethyl ether solution (8.8 mL, 17.6 mmol) was added. added.
  • the resulting suspension was stirred at room temperature for 1 hour, then treated with 1,4-dioxane (5.4 mL), stirred for an additional hour, and then cooled to -35 ° C.
  • Example 11 Preparation of diethylzinc from ethylmagnesium chloride and zinc chloride and asymmetric addition to imine 1e in dibutyl ether
  • a 1.0 M zinc chloride diethyl ether solution (9.0 mL, 9.0 mmol) was diluted with dibutyl ether (35.6 mL), and a 2.0 M ethylmagnesium chloride diethyl ether solution (8.8 mL, 17.6 mmol) was added. added.
  • the resulting suspension was stirred at room temperature for 1 hour, then treated with 1,4-dioxane (5.4 mL), stirred for an additional hour, and then cooled to -35 ° C.
  • Example 14 Preparation of ethyl magnesium bromide from ethyl bromide and magnesium and preparation of diethyl zinc by reaction with zinc chloride and asymmetric addition to 1 g of imine in dibutyl ether
  • Ethyl bromide (2.05 g, 18.5 mmol) was added to a flask containing magnesium (428 mg, 17.6 mmol), dibutyl ether (23.4 mL) and iodine (ca. 10 mg) and the mixture was stirred for 1 hour at room temperature.
  • the resulting gray solution was added to a flask containing zinc chloride (1.2 g, 9 mmol) and dibutyl ether (30 mL) at room temperature.
  • the dialkylzinc produced in the system can be used as it is for the subsequent addition reaction of the imine compound without isolation, the dialkylzinc can be used in the reaction in a stable state without being decomposed.
  • an amine compound can be produced by a simple and industrially advantageous method because there is no need for an apparatus or equipment for maintaining an anhydrous state. Therefore, the production method of the present invention can be an industrially useful production method for optically active synthetic intermediates such as pharmaceuticals and agricultural chemicals.

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Abstract

La présente invention concerne un procédé de production d'un composé aminé (5) pouvant être mis en œuvre même en présence de sels inorganiques. Le procédé comprend les étapes suivantes : étape (1) R-Mg-X1 est mis à réagir avec X2-Zn-X2 ; étape (2) un produit réactionnel contenant R-ZN-R, un composé d'imine (1), un composé contenant du cuivre et un composé de phosphoramidite sont mélangés pour que le composé R-ZN-R réagisse avec le composé d'imine (1) ; et étape (3) le composé aminé protégé sur l'azote (2) est déprotégé.
PCT/JP2012/061303 2011-04-25 2012-04-20 Procédé de production d'un composé aminé Ceased WO2012147897A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2895981A (en) * 1952-07-03 1959-07-21 Campbell Pharmaceuticals Inc Aryl esters of acid phosphorus compounds
JPH05271161A (ja) * 1992-03-10 1993-10-19 Nippon Alkyl Alum Kk 光学活性アミンの製造方法
WO1998039276A1 (fr) * 1997-03-06 1998-09-11 Mitsui Chemicals Inc. Procede de production d'amines actives optiquement
JP2000256305A (ja) * 1999-03-10 2000-09-19 Sumitomo Chem Co Ltd 光学活性アミン化合物の製造法
CN1868594A (zh) * 2005-05-27 2006-11-29 中国科学院大连化学物理研究所 一类亚磷酰胺配体及其制备方法和应用

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9626635D0 (en) * 1996-12-21 1997-02-12 Zeneca Ltd Zinc reagent and synthesis
DE602004025458D1 (de) * 2003-04-18 2010-03-25 Schering Corp SYNTHESE VON 2-HYDROXY-N,N-DIMETHYL-3-ii2-i1(R)-(5-METHYL-2-FURANYL)PROPYL AMINO -3,4-DIOXO-1-CYCLOBUTEN-1-YL AMINO BENZAMID
WO2005058805A1 (fr) * 2003-12-17 2005-06-30 Sumitomo Chemical Company, Limited Procede de production de compose amine optiquement actif
EP2155759A4 (fr) * 2007-05-07 2012-10-17 Valorisation Rech Soc En Commandite Méthodes de préparation de composés de diorganozinc
WO2010100990A1 (fr) * 2009-03-04 2010-09-10 国立大学法人名古屋大学 Procédé de production de produits d'addition nucléophile par réaction de grignard et réactif d'addition nucléophile

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2895981A (en) * 1952-07-03 1959-07-21 Campbell Pharmaceuticals Inc Aryl esters of acid phosphorus compounds
JPH05271161A (ja) * 1992-03-10 1993-10-19 Nippon Alkyl Alum Kk 光学活性アミンの製造方法
WO1998039276A1 (fr) * 1997-03-06 1998-09-11 Mitsui Chemicals Inc. Procede de production d'amines actives optiquement
JP2000256305A (ja) * 1999-03-10 2000-09-19 Sumitomo Chem Co Ltd 光学活性アミン化合物の製造法
CN1868594A (zh) * 2005-05-27 2006-11-29 中国科学院大连化学物理研究所 一类亚磷酰胺配体及其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
COTE, ALEXANDRE ET AL.: "General method for the expedient synthesis of salt-free diorganozinc", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 130, no. 9, 2008, pages 2771 - 2773 *

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